Antiinflammatory 2-aminomethyl-6-trihalomethylphenols

ABSTRACT

2-Aminomethylphenol products and their non-toxic, pharmaceutically acceptable salts useful in the treatment of edema and inflammation are disclosed. The products may be prepared by treating an N-(2-hydroxybenzyl)carboxamide with an aqueous solution of an acid or a base.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation, of application Ser. No. 600,990 filed Aug. 1,1975 now U.S. Pat. No. 3,979,361, which is a continuation-in-part ofco-pending application Ser. No. 444,200 filed Feb. 20, 1974, which isnow abandoned, which in turn is a continuation-in-part of Ser. No.120,730 filed Mar. 3, 1971, now U.S. Pat. No. 3,794,734.

SUMMARY OF THE INVENTION

This invention relates to 2-aminomethylphenols useful in the treatmentof edema and inflammation, processes for preparing same, compositionsand methods of treating inflammation. Particularly, it relates to2-aminomethyl-4-lower alkyl-6-trihalomethylphenol or its non-toxic,pharmaceutically acceptable salts and its uses as described.

Pharmacological studies employing rats and dogs as the experimentalanimals indicate that the instant products and compositions containingthe active products are effective diuretic and saluretic agents whichcan be used in the treatment of conditions associated with electrolyteand fluid retention. When administered in therapeutic dosages inconventional vehicles, the instant products effectively reduce theamount of sodium and chloride ions in the body, lower dangerous excessesof fluid level to acceptable levels and, in general, alleviateconditions usually associated with edema. Further, studies employing themouse ear test and the carrageenin edema test commonly employed for thediscovery of antiinflammatory activity such as is found in indomethacinand the antiinflammatory steroids indicate that the compounds of thisinvention are effective antiinflammatory agents useful both topicallyand systemically.

The compounds of this invention have the following formula: ##STR1##wherein X¹ is C₁₋₇ lower alkyl such as methyl, ethyl, n-propyl, n-butyl,sec-butyl, tert-butyl, 1-methylhexyl and the like, cycloalkyl, forexample, cycloalkyl containing 5 to 6 carbon atoms such as cyclopentyl,cyclohexyl and the like;

X² is trihalomethyl such as trifluoromethyl, trichloromethyl and thelike.

Also included are their non-toxic, pharmaceutically acceptable salts,preferably the non-toxic, pharamaceutically acceptable acid additionsalts derived from hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, methanesulfonic acid, isethionic acid and the like; saltsmay also be prepared from the alkali metal bases such as sodiumhydroxide, potassium hydroxide and the like.

A preferred embodiment of this invention relates to compounds and theiruse having the following formula: ##STR2## wherein X³ is lower alkylparticularly tert-butyl; and

X⁴ is trifluoromethyl and the non-toxic, pharmaceutically acceptableacid addition salts thereof.

Compositions containing this class of compounds exhibit particularlygood diuretic, saluretic and antiinflammatory activity and represent apreferred sub-group within the scope of the invention.

The compositions containing the 2-aminomethylphenols (I) as the activeingredient and also the 2-aminomethylphenols (I) themselves useful asdiuretic and saluretic agents, can be administered in a wide variety oftherapeutic dosages in conventional vehicles as, for example, by oraladministration in the form of a tablet or capsules, by intravenousinjection or oral solutions or suspensions. Also, the daily dosage ofthe products may be varied over a wide range varying from 50 to 2,000mg. The product is preferably administered in subdivided doses in theform of scored tablets containing 5, 10, 25, 50, 100, 150, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugis ordinarily supplied at a dosage level of from about 1 mg. to about 50mg./kg. of body weight. Preferably the range is from about 1 mg. to 7mg./kg. of body weight. These dosages are well below the toxic or lethaldose of the products. A suitable suit dosage form of the products ofthis invention can be administered by mixing 50 milligrams of a2-aminomethylphenol (I) or a suitable salt thereof, with 149 mg. oflactose and 1 mg. of magnesium stearate and placing the 200 mg. mixtureinto a No. 1 gelatin capsule. Similarly, by employing more of the activeingredient and less lactose, other dosage forms can be put up in No. 1gelatin capsules and, should it be necessary to mix more than 200 mg. ofingredients together, larger capsules may be employed. Tablets may beprepared by mixing the active ingredient with conventional tabletingingredients such as calcium phosphate, lactose, corn starch or magnesiumstearate. The liquid forms in which the active ingredients may beincorporated include suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. Other dispersing agents which may beemployed include glycerin and the like. For parenteral administrationsterile suspensions and solutions are desired. Isotonic preparationswhich generally contain a suitable preservative are employed whenintravenous administration is desired.

The compositions containing the 2-aminomethylphenols as the activeingredient and also the 2-aminomethylphenols themselves, useful astopical antiinflammatory agents are particularly effective in topicaltreatment of dermatological disorders and like conditions, such asdermatitis (actinic, atopic, contact, eczematoid, seborrheic andstasis), dermatitis herpetiformis, lichen planus, neurodermatitis,intertrigo, lichen simplex chronicus, pruritus and psoriasis, as well asfor topical treatment of inflammations of the respiratory and intestinalmucosa such as allergic rhinitis, bronchitis, bronchial asthma,bronchiectasis, colitis and the like. These 2-aminomethylphenols areordinarily administered in the form of a pharmaceutical compositioncomprising the active compound in combination with a pharmacologicallyacceptable carrier adapted for topical administration. These topicalpharmaceutical compositions may be in the form of a cream, ointment, gelor aerosol formulation adapted for application to the skin for treatmentof dermatoses; or it may be in the form of a solution, suspension oraerosol adapted for topical spray application to respiratory passagesfor treatment of nasal allergies, bronchial inflammations, and the like;or in the form of suppositories or enclosed in enteric capsules fortreatment of intestinal inflammations. For treatment of dermatologicaldisorders, these topical pharmaceutical compositions containing thepresently invented 2-aminomethylphenols ordinarily include about 0.01%to 15%, preferably about 5% of the active compound, in admixture with95% of gel vehicle comprising water, at least one organic solvent, andat least one thickening agent. The water ordinarily constitutes fromabout 8% to 18% of the gel vehicle, preferably about 13%. The organicsolvent ordinarily constitutes about 60% to 90% of the gel vehicle.Representative solvents are ethyl alcohol, isopropyl alcohol, propyleneglycol, glycerine, 2-octyl dodecanol and methyl pyrrolidine, andpreferably isopropyl alcohol; propylene glycol mixtures at a ratio of0.5 to 0.6 parts isopropyl alcohol to 1.0 part propylene glycol. Thesolubility of the 2-aminomethylphenol compound in the solvent systemselected should be such as to obtain maximum partitioning of the activecompound from the vehicle to the skin. The thickening agent, preferablyhydroxyethyl cellulose, hydroxypropyl cellulose, and the like,ordinarily constitutes from 0.5 to 4.0% of the gel vehicle. Optionally,a stabilizing agent, such as disodium edetate, sodium citrate,dipotassium edetate, citric acid, and the like, in the proportion ofabout 0.02% to 0.1% of the gel vehicle may be employed, if desired.

A preferred topical pharmaceutical composition is prepared as follows:About 2.60 g. of hydroxypropyl cellulose is added to a solution of 0.05g. of disodium edetate in 13.00 g. purified water while agitating themixture and maintaining the temperature at about 60° C., and theagitation is continued until the hydroxypropyl cellulose is completelydispersed and wetted. To the resulting dispersed mixture is added, withagitation, a solution containing 5.0 g. of, for example,2-aminomethyl-4-t-butyl-6-trifluoromethylphenol hydrochloride dispersedin a mixture of 30.00 g. of anhydrous isopropyl alcohol and 49.35 g. ofpropylene glycol. The resulting gel mixture is stirred vigorously atroom temperature for a period of approximately 15 minutes therebyforming a pharmaceutical composition adapted for the treatment oftopical antiinflammatory conditions.

The compositions containing the 2-aminomethylphenols as the activeingredient and also the 2-aminomethylphenols themselves, useful assystemic antiinflammatory agents may be orally, rectally or parenterallyadministered to patients in a non-toxic pharmaceutically acceptablecarrier.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin and acacia. Exemplary of liquid carriers arepeanut oil, olive oil, sesame oil and water. Similarly, the carrier ordiluent may include a time delay material such as glyceryl monostearateor glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup, an aqueous solution or a liquid suspension. Suppositories may beprepared in a conventional manner by mixing the compounds of thisinvention with a suitable non-irrating excipient which is solid at roomtemperature, but liquid at the rectal temperature. Such materials arecocoa butter and polyethylene glycol. Gels and lotions for topicalapplication may be prepared in a conventional manner. The activecompounds are administered in an amount sufficient to treatinflammation; that is, to reduce inflammation. Advantageously, thecompositions will contain the active ingredient in an amount of fromabout 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5 g. perpatient per day), preferably from about 1 mg. to 15 mg./kg. body weightper day (50 mg. to 1 g. per patient per day).

Various tests have been carried out to show the ability of the compoundsdescribed herein to exhibit reactions that can be correlated withantiinflammatory activity in humans. One such test used is thecarrageenin test which is known to correlate well with antiinflammatoryactivity in humans and is a standard test used to determineantiinflammatory activity. This test shows the ability of compounds toinhibit edema induced by injection of an inflammatory agent into thetissue of the foot of a rat against non-inflammed controls. This test isgenerally outlined by C. A. Winter, Proc. Soc. Exptl. Biolog. & Med.,1962, III, 544. The correlation has been shown by the activities ofcompounds known to be clinically active, including Indocin, Asprin,Butazolidin, Tandearil, Cortone, Hydrocortone, Decadron.

The following examples are illustrative of how to prepare variouscompositions containing the active ingredients of this invention.However, the examples are merely illustrative and should not beconstrued as limiting the scope of the invention.

EXAMPLE 1 Tablets containing 100 mg. of active ingredient per tablet

    ______________________________________                                                             Per Tablet                                               ______________________________________                                        2-Aminomethyl-4-tert-butyl-6-                                                  trifluoromethylphenol hydro-                                                  chloride              100 mg.                                                Calcium Phosphate      40 mg.                                                 Lactose                38 mg.                                                 Corn Starch            20 mg.                                                 Magnesium Stearate     2 mg.                                                                         200 mg.                                                ______________________________________                                    

The 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride ismixed with the calcium phosphate and lactose for ten minutes and thenpassed through a mill to reduce the particle size. The combinedingredients are remixed for five minutes and corn starch is passedthrough a No. 60 sieve (U.S. Sieve Series) onto the ingredients. Thecombined ingredients are again remixed for five minutes and thenmagnesium stearate is added through a No. 60 sieve. After remixing fortwo minutes the ingredients are compressed into tablets.

Similar dry-filled capsules, tablets, elixirs and suspensions can beprepared by replacing the active ingredient of the above example by anyof the other compounds described in the foregoing general disclosure andthe specific examples which follow.

EXAMPLE 2

A mixture of 250 parts of2-aminomethyl-4-tertbutyl-6-trifluoromethylphenol hydrochloride and 25parts of lactose is granulated with suitable water, and to this is added100 parts of maize starch. The mass is passed through a 16 mesh screen.The granules are dried at a temperature below 60° C. The dry granulesare passed through a 16 mesh screen, and mixed with 3.8 parts ofmagnesium stearate. They are then compressed into tablets suitable fororal administration.

25, 100 or 500 parts of2-aminomethyl-4-tertbutyl-6-trifluoromethylphenol hydrochloride may beused in place of 250 parts above to produce tablets suitable for oraladministration according to the method of this invention.

EXAMPLE 3

A mixture of 50 parts of 2-aminomethyl-4-methyl-6-trifluoromethylphenolhydrochloride, 3 parts of the calcium salt of lignin sulfonic acid and237 parts of water is ball-milled until the size of substantially all ofthe particles is less than 10 microns. The suspension is diluted with asolution containing 3 parts of sodium carboxymethylcellulose and 0.9parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water.There is thus obtained an aqueous suspension suitable for oraladministration for therapeutic purposes.

2-aminomethyl-4-tert-butyl-6-trichloromethylphenyl hydrochloride may beused in place of the allylamino compound in the above example to obtaina suspension suitable for oral administration.

EXAMPLE 4 1. Tablets - 10,000 scored tablets for oral use, eachcontaining 500 mg. of active ingredient are prepared from the followingingredients:

    ______________________________________                                                                Gm.                                                   ______________________________________                                        2-aminomethyl-4-tert-butyl-6-                                                  trifluoromethylphenol                                                         hydrochloride            5000                                                Starch, U.S.P.            350                                                 Talc, U.S.P.              250                                                 Calcium Stearate          35                                                  ______________________________________                                    

The 2-aminomethylphenol compound is granulated with a 4% w./v. aqueoussolution of methylcellulose U.S.P. (1500 cps.). To the dried granules isadded a mixture of the remainder of the ingredients and the finalmixture compressed into tablets of proper weight. 2. Capsules - 10,000two-piece hard gelatin capsules for oral use, each containing 250 mg. ofactive ingredient are prepared from the following ingredients:

    ______________________________________                                                                Gm.                                                   ______________________________________                                        2-aminomethyl-4-tert-butyl-6-                                                  trifluoromethylphenol                                                         hydrochloride            2500                                                Lactose, U.S.P.           1000                                                Starch U.S.P.             300                                                 Talc U.S.P.               65                                                  Calcium Stearate          25                                                  ______________________________________                                    

The 2-aminomethyl compound is mixed with the starch lactose mixturefollowed by the talc and calcium stearate. The final mixture is thenencapsulated in the usual manner. Capsules containing 10, 25, 50 and 100mg. of active ingredient are also prepared by substituting 100, 250, 500and 1000 gm. for 2500 gm. in the above formulation. 3. Soft elasticcapsules - One-piece soft elastic capsules for oral use, each containing500 mg. of active material are prepared in the usual manner by firstdispersing the active material in sufficient corn oil to render thematerial capsulatable. 4. Aqueous suspension - An aqueous suspension fororal use containing in each 5 ml., 1 gm. of active ingredient isprepared from the following ingredients:

    ______________________________________                                                               Gm.                                                    ______________________________________                                        2-aminomethyl-4-tert-butyl-6-                                                  trifluoromethylphenol                                                         hydrochloride           2000                                                 Methylparaben, U.S.P.    7.5                                                  Propylparaben, U.S.P.    2.5                                                  Saccharin sodium         12.5                                                 Glycerin                 3000                                                 Tragacanth powder        10                                                   Orange oil flavor        10                                                   F.D. & C. orange dye     7.5                                                  Deionized water, q.s. to 10,000 ml.                                           ______________________________________                                    

EXAMPLE 5 Gel Formulation

0.1 mg. disodium edetate

13.0 mg. of purified H₂ 0

300 mg. isopropanol

26 mg. hydroxypropylcellulose

50 mg. 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride

q.s.a.d. 1 gm. propylene glycol

EXAMPLE 6 Ointment Formulation

50 mg. wool alcohols B.P.

150 mg. amichol C

350 mg. white wax

50 mg. 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride

q.s.a.d. 1 gm. isopropyl myristate

The 2-aminomethylphenols (I) described above may be prepared by one oftwo methods which comprises (1) treating anN-(2-hydroxybenzyl)carboxamide (II) with an aqueous solution in thepresence of an acid or base or (2) subjecting a substituted2-hydroxybenzaldehyde (III) to reduction.

The first of the above-mentioned processes comprises treating anN-(2-hydroxybenzyl)carboxamide (II, infra) with an aqueous solution inthe presence of an acid, preferably a mineral acid such as hydrochloricacid, hydrobromic acid, sulfuric acid, hydroiodic acid and the like; inaddition to the mineral acids, bases may also be employed, for example,the alkali metal bases such as sodium hydroxide, potassium hydroxide andthe like. Any solvent which is inert or substantially inert to thereactants may be employed such as ethanol, acetic acid and the like. Thereaction may be conducted at a temperature in the range of from about20° C. to about 110° C. for a period of time of from about 15 minutes toabove five hours; however, the reaction is generally conducted at thereflux temperature of the particular solvent employed for a period oftime of about one and one-half hours. The following equation illustratesthis reaction employing a mineral acid, HR¹, such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and the like. ##STR3##wherein X¹ and X² are as defined for Formula I above; R is an acylradical, for example, (C₁₋₅ alkanoyl), formyl, haloacetyl such aschloroacetyl and the like, carbamoyl, mononuclear aroyl such as benzoyland the like, hydroxy substituted mononuclear aroyl such aso-hydroxybenzoyl and the like or trihalomethylcarbonyl such astrichloromethylcarbonyl and the like and R¹⁻ is the anion derived froman acid, for example, a mineral acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and the like. Theproduct is usually obtained in the form of an acid addition salt and thefree amine can be generated by known neutralization methods.

The second method for preparing the 2-aminomethylphenols (I) comprisessubjecting a substituted 2-hydroxybenzaldoxime (III, infra) toreduction, for example, by hydrogenation such as catalytic hydrogenationemploying a noble metal such as rhodium, ruthenium and the like,preferably on a carrier such as carbon and the like. The reduction isgenerally conducted employing as the solvent a lower alkanol such asethanol, methanol and the like in the presence of mineral acid such assulfuric acid and the like. The following equation illustrates thisprocess: ##STR4## wherein X¹ and X² and R¹⁻ are as defined above. Theproduct is usually obtained in the form of an acid addition salt and thefree amine can be generated by known neutralization methods.

The N-(2-hydroxybenzyl)carboxamides (II, supra) employed as startingmaterials in the preparation of the 2-aminomethylphenols (I) areprepared by treating an appropriately substituted phenol (IV, infra)with an N-hydroxymethylcarboxamide, for example, N-hydroxymethylurea,2-halo-N-hydroxymethylacetamide such as2-chloro-N-hydroxymethylacetamide and the like, N-hydroxymethylmononuclear arylcarboxamide such as N-hydroxymethylbenzamide and thelike, N-hydroxymethyl hydroxy substituted arylcarboxamide such asN-hydroxymethylsalicylamide and the like orN-hydroxymethyltrihaloacetamide such asN-hydroxymethyltrichloroacetamide and the like in the presence of astrong mineral acid such as hydrochloric acid, sulfuric acid and thelike. The reaction may be conducted employing as the solvent an excessof the mineral acid employed or with a solvent which is inert orsubstantially inert to the reactants employed, for example, a loweralkanol such as ethanol and the like or a lower alkanoic acid such asacetic acid and the like. The N-(2-hydroxybenzyl)carboxamides (II) maybe isolated and purified; however, it has been found that by employingthe crude N-(2-hydroxybenzyl)carboxamides satisfactory results areobtained. The following equation illustrates this process: ##STR5##wherein X¹, X² and R are as defined above.

The 2-hydroxybenzaldoximes (III, supra) employed may be prepared bytreating an appropriate phenol with chloroform in the presence of a baseor a mixture of bases such as sodium carbonate and calcium hydroxidewhich yields the correspondingly substituted 2-hydroxybenzaldehyde thenthe 2-hydroxybenzaldehyde (V, infra) is treated with a hydroxylaminehydrohalide such as hydroxylamine hydrochloride and the like in thepresence of a base such as sodium acetate and the like. This reaction isgenerally conducted in a lower alkanol solvent such as ethanol and thelike. The reaction is conveniently conducted at the boiling point of theparticular solvent employed. The following equation illustrates thisprocess: ##STR6## wherein X¹ and X² are as defined above.

The following examples illustrates the preparation of the2-aminomethylphenols (I). However, the examples are illustrative onlyand it will be apparent to those having ordinary skills in the art thatall of the products embraced by Formula I, supra, may also be preparedin an analogous manner by substituting the appropriate startingmaterials for those set forth in the examples.

EXAMPLE 7 Preparation of2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride A.Preparation of 2-trifluoromethyl-4-tert-butylphenol

A mixture of 2-rifluoromethylphenol (25 g., 0.15 moles), tert-butylalcohol (12 g., 0.16 mole), trifluoroacetic acid (100 ml.) and 96%sulfuric acid (2 ml.) is stirred at about 20° C for 48 hours. Themixture then is evaporated as far as possible under reduced pressure at35°-40° C. The residue is dissolved in benzene (500 ml.) and thesolution is washed with water, saturated NaHCO₃ solution and saturatedsalt brine and dried over anhydrous Mg SO₄. The dried solution is againevaporated under reduced pressure and the temperature is finally raisedto 140°-150° C under 65 mm. pressure to remove unchanged2-trifluoromethylphenol. The residue is distilled at 65 mm. aftercollecting a small fore-run (75% unchanged starting phenol and 25%product), 2-trifluoromethyl-4-tert-butylphenol (13.6 g) is collected at120°-132° C as a pale pink oil that is 98% pure by gas liquidchromatography analysis and can be used directly in the next step.

Following the above procedure but using an equivalent amount ofisopropyl alcohol, sec-butyl alcohol or cyclohexyl alcohol in place oftert-butyl alcohol, there is produced an equivalent amount of2-trifluoromethyl-4-isopropylphenol, 2-trifluoromethyl-4-sec-butylphenolor 2-trifluoromethyl-4-cyclohexylphenol.

B. Preparation of 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenolhydrochloride

2-Trifluoromethyl-4-tert-butylphenol (15.6 g., 0.062 mole) is dissolvedin a mixture of glacial acetic acid (200 ml.) and 96% sulfuric acid (150ml.). The mixture is stirred and finely powderedN-hydroxymethyl-2-chloroacetamide (8 g., 0.065 mole) is added in smallportions at 20°-25° C. Stirring then is continued for 5 hours afterwhich the mixture is poured into water (3 1.). The2-(2-chloroacetamidomethyl)-4-tert-butyl-6-iodophenol that separates iscollected and dried by suction to obtain a solid (19 g., m.p. about85°-100° C).

The solid, the 2-chloroacetyl derivatives of2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride, isdissolved in a mixture of ethanol (75 ml.) and 12 N hydrochloric acid(25 ml.). The mixture is refluxed for 5 hours, cooled to 20° C anddiluted with 12 N hydrochloric acid (150 ml.). Upon cooling to -20° C,the product separates (14 g.). It is crystallized from ethanol-12 Nhydrochloric acid (1:4) to obtain pure2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride, m.p.202°-204° C.

Anal. Calc.: C,50.80; H,6.04; N,4.94. Found: C,50.75; H,6.01; N,4.72.

Following the above procedure but using an equivalent amount of2-trifluoromethyl-4-isopropylphenol, 2-trifluoromethyl-4-sec-butylphenolor 2-trifluoromethyl-4-cyclohexylphenol in place of2-trifluoromethyl-4-tert-butylphenol, there is obtained an equivalentamount of 2-aminomethyl-4-isopropyl-6-trifluoromethylphenolhydrochloride, 2-aminomethyl-4-sec-butyl-6-trifluoromethylphenolhydrochloride or 2-aminomethyl-4-cyclohexyl-6-trifluoromethylphenolhydrochloride.

EXAMPLE 8

2-Aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride

A. 3-Trifluoromethyl-5-tert-butyl salicylaldehyde

0.1 mole of 2-trifluoromethyl-4-tert-butylphenol and 0.1 mole ofhexamethylenetretramine is dissolved in trifluoroacetic acid (150 ml.)and the mixture refluxed for 8 hours. After this time, 150 ml. of waterand 50 ml. of concentrated hydrochloric acid is added. This mixture isthen refluxed for 1/2 hour. The reaction mixture is cooled and extractedwith ether (5 × 50 ml.) and the ether extract is dried over magnesiumsulfate. The ether is evaporated and the residue is crystallized fromethanol to yield 3-trifluoromethyl-5-t-butyl salicylaldehyde.

B. 3-Trifluoromethyl-5-tert-butyl salicylaldehyde oxime

0.05 moles of the aldehyde from Step A, 0.12 moles of hydroxylaminehydrochloride and sodium acetate (0.12 moles) are dissolved in a mixtureof ethanol (100 ml.) and water (30 ml.). The reaction mixture isrefluxed for 2 hours, cooled and water added until no more precipitateforms. The solid that separates is crystallized from ethanol to yield3-trifluoromethyl-5-tert-butyl salicylaldehyde oxime.

C. 2-Aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride

The oxime of Step B (0.02 moles) is dissolved in ethanol (200 ml.) towhich concentrated H₂ SO₄ (0.05 moles) is added. To this solution isadded 5% Ruthenium on carbon (100 mg.). The mixture is hydrogenated at40 lbs./sq. in. until the calculated amount of hydrogen is taken up. Thecatalyst is removed by filtration and the filtrate is evaporated todryness, giving the sulphate salt of the title compound. The sulfate issuspended in water and neutralized with 28% ammonium hydroxide. The freebase is taken up in ethanol and an equivalent amount of 6N ethanolic HClis added. On addition of ether the title product is precipitated. Theprecipitate is collected and crystallized from a mixture of ethanol andconcenrated HCl.

What is claimed is:
 1. A pharamaceutical composition comprising anantiinflammatory effective amount of a compound of the formula: ##STR7##wherein X¹ is C₁₋₇ lower alkyl, or cycloalkyl containing 5 to 6 carbonatoms; and X² is trifluoromethyl; or the non-toxic pharamaceuticallyacceptable salts thereof in a pharamceutically acceptable carrier. 2.The composition of claim 1 wherein X¹ is tert-butyl.